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Introduction: Developmental and epileptic encephalopathies (DEE) is a group of epilepsies where the epileptic activity, seizures and the underlying neurobiology contributes to cognitive and behavioral impairments. Uncovering the causes of DEE is important in order to develop guidelines for treatment and follow-up. The aim of the present study was to describe the clinical picture and to identify genetic causes in a patient cohort with DEE without known etiology, from a Norwegian regional hospital. Methods: Systematic searches of medical records were performed at Drammen Hospital, Vestre Viken Health Trust, to identify patients with epilepsy in the period 1999-2018. Medical records were reviewed to identify patients with DEE of unknown cause. In 2018, patients were also recruited consecutively from treating physicians. All patients underwent thorough clinical evaluation and updated genetic diagnostic analyses. Results: Fifty-five of 2,225 patients with epilepsy had DEE of unknown etiology. Disease-causing genetic variants were found in 15/33 (45%) included patients. Three had potentially treatable metabolic disorders (SLC2A1, COQ4 and SLC6A8). Developmental comorbidity was higher in the group with a genetic diagnosis, compared to those who remained undiagnosed. Five novel variants in known genes were found, and the patient phenotypes are described. Conclusion: The results from this study illustrate the importance of performing updated genetic investigations and/or analyses in patients with DEE of unknown etiology. A genetic cause was identified in 45% of the patients, and three of these patients had potentially treatable conditions where available targeted therapy may improve patient outcome.
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BACKGROUND: CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) syndrome is caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. Other mutations in this gene can cause a spectrum of overlapping phenotypes including alternating hemiplegia of childhood, rapid onset dystonia parkinsonism, early infantile epileptic encephalopathy and fever induced paroxysmal weakness and encephalopathy. The phenotype is still mistaken for mitochondrial/metabolic disorders and follow up studies are scare. CASE PRESENTATION: We report a 20 year old Norwegian male with ataxia, sensorineural deafness and visual loss. Before the age of five he experienced three fever related episodes of acute neurological deterioration when he temporarily lost his acquired motor skills and developed persistent gait and limb ataxia. In childhood, he developed bilateral optic atrophy and bilateral sensorineural hearing loss. Motor skills improved and at age 20 the patient showed a mild ataxia, hearing loss and reduced vision. A c.2452G > A mutation in the ATP1A3 gene was identified and CAPOS syndrome was confirmed. CONCLUSIONS: This is the first Norwegian patient reported with CAPOS syndrome. Our patient had a de novo, previously identified ATP1A3 mutation. The combination of recurrent episodes of fever related ataxia, loss of motor skills in early childhood, and early onset hearing and vision loss is typical of CAPOS syndrome. Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode.